EP1312365A1 - Ptéridinones pour le traitement des dysfonctions érectiles - Google Patents

Ptéridinones pour le traitement des dysfonctions érectiles Download PDF

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Publication number
EP1312365A1
EP1312365A1 EP02002882A EP02002882A EP1312365A1 EP 1312365 A1 EP1312365 A1 EP 1312365A1 EP 02002882 A EP02002882 A EP 02002882A EP 02002882 A EP02002882 A EP 02002882A EP 1312365 A1 EP1312365 A1 EP 1312365A1
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EP
European Patent Office
Prior art keywords
ethyl
pteridinone
methyl
pde
tricyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02002882A
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German (de)
English (en)
Inventor
Jens Dr. Schröder
Farid Dr. Saad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jenapharm GmbH and Co KG
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Jenapharm GmbH and Co KG
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Filing date
Publication date
Application filed by Jenapharm GmbH and Co KG filed Critical Jenapharm GmbH and Co KG
Publication of EP1312365A1 publication Critical patent/EP1312365A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the invention relates to the use of special pteridinones and their pharmaceutically acceptable salts for the treatment of erectile dysfunction.
  • Erectile dysfunction is a major medical problem worldwide for adult men of reproductive and sexually active age. Impotence can be defined as a man's inability to copulate or ejaculate, or both together.
  • the Massachusetts Male Aging Study found the following distribution of moderate and severe erectile dysfunction: 22% of 40-year-olds, 32% of 50-year-olds, 40% of 60-year-olds and 49% of 70-year-old men are affected. An estimated 100 to 200 million people worldwide are affected. With increasing life expectancy, this number will continue to grow in the coming years.
  • cAMP and cGMP are made from GTP and ATP under the influence of the enzymes guanylate and adenylate cyclase produced.
  • PDE phosphodiesterases
  • the present invention is therefore based on the object of the symptoms of erectile Dysfunction without being able to treat the above disadvantages.
  • erectile dysfunction can be defined as that Inability of the man to copulate or ejaculate, or both together. Ultimately, with erectile dysfunction there is either no or only a reduced one Determine penile erection.
  • the present invention is now based on the completely surprising finding that erectile dysfunction particularly well with the pteridinones and / or described above whose pharmaceutically acceptable salts can be treated. It was advantageously observed a very pronounced effect, the effect over a lasted a very long time.
  • Pteridinones as used according to the invention are per se Known compounds, as described for example in EP 0 429 149 A1. There the preparation of pteridinones is also explained in detail.
  • EP 0 429 149 A1 describes turned off the cardiovascular properties of the pteridinones described therein, it finds but there is no evidence in it that pteridinones are used to treat erectile dysfunction can be used.
  • the inventive pteridinones used are non-selective phosphodiesterase inhibitors, i.e. around mixed-functional PDE inhibitors that inhibit more than one of the known PDE subtypes. At least the PDE subtypes IV and V are favorably inhibited and can additionally other PDE subtypes, in particular PDE I and / or PDE VI, can also be inhibited. So for example, it was found that the compound 9-ethyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) -7-methyl-4- (2-propyl) imidazo [5,1-h] pteridin-6 (5H) -one PDE types I, IV, V and VI inhibits.
  • the pteridinone used according to the invention by 9-ethyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) -7-methyl-4- (2-propyl) imidazo [5,1-h] pteridin- 6 (5H) -one, 2 - [[3,4-dimethoxyphenyl) methyl] amino] -4,9-diethyl-7-methylimidazo [5,1-H] pteridin-6 (5H) -one, 9-ethyl-2- (2-ethyl-4-methyl-1H-imidazol-1-yl) -7-methylimidazo [5,1-H] pteridin-6 (5H) -one or 9- (2-cyclohexylethyl) -4-ethyl-2- (1H-imidazol-1-yl) imidazo [5,1-H] pteridin-6 (5H) -one
  • the drugs can be 1 pteridinone or more, from each other contain various pteridinones.
  • compositions Pteridinone can be used.
  • Such salts are in particular phosphates, sulfates, citrates, Chlorides and bromides as well as hydrochlorides (addition of HCl to pteridinones).
  • the Medicaments produced according to the invention can contain 1 salt or more from one another have different salts of pteridinones.
  • the drug can be 1 pteridinone or several pteridinones as free bases and / or one or more pteridinones as pharmaceutical contain acceptable salts.
  • NO donor is understood to mean compounds of any kind which release NO in the body can.
  • NO donors are S-nitroso-N-acetylpenicillamine or Sodium nitroprusside.
  • the drug can have several different NO donors exhibit.
  • the drug can be designed so that it is the administration of the NO donor before, together with or after application of the pteridinones.
  • NO donor for example, given to the patient together with the pteridinone, these can be given two active ingredients in a pharmaceutical formulation, for example a tablet, present together.
  • NO donor and pteridinone are advantageously chosen so that they don't react with each other.
  • the drug can be designed in the form of a kit with part of the kit containing pharmaceutical formulations containing only the pteridinone and another part of the kit has such formulations that only the NO donor include.
  • the drug is favorably suitable for oral or parenteral administration, including topical, rectal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intrabuccal or sublingual application.
  • the Medicaments produced according to the invention can be used in addition to those described above Active ingredients still have conventional carriers and diluents.
  • the drugs can with the usual solid or liquid carriers or diluents and Usually used pharmaceutical-technical auxiliaries according to desired type of application with a suitable dosage in a known manner become.
  • the dose can be 0.05 mg to 100 mg per pharmaceutical formulation.
  • An orally administrable drug for example tablets or Dragees, because the application can be done in a particularly simple manner.
  • Administration can be performed if necessary, e.g. daily.
  • Example 1 Determination of the phosphodiesterase subtype profile
  • PDE cyclic nucleotide phosphodiesterases
  • PDE activity was measured in a reaction medium containing 40 mM Tris-HCl (pH 8.0), 5 mM MgCl 2 , 1 mM dithiothreitol and 0.2 ⁇ M [ 3 H] cyclic GMP.
  • the tricyclic pteridinone was dissolved in DMSO (2.5%). At this DMSO concentration the enzyme activity was inhibited to about 10%.
  • the IC 50 values for the tricyclic pteridinone were determined on the basis of dose-response curves in which the concentration was in the range from 1 nM to 10 ⁇ M (whole log increments). For each PDE isozyme investigated, at least two IC 50 determinations were carried out on different days.
  • the tricyclic pteridinone shows an inhibitory activity against the PDE types I, IV, V and VI. Inhibition of PDE I and V increases cGMP, while inhibition of PDE IV increases cAMP.
  • the tissues were pretreated with indomethacin (10 ⁇ M) to produce cyclooxygenase effects remove.
  • indomethacin 10 ⁇ M
  • phenylephrine 10 ⁇ M
  • Contractions induced After the phenylephrine-induced contraction is permanent Had reached the tricyclic pteridinone (Pt) (Fig. 1a and 1b) or the Nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) added (Fig. 2).
  • Example 3 Cat model of male erectile dysfunction
  • a central catheter was placed in the internal carotid artery to perform arterial blood gas analysis (ABGA) and record systemic blood pressure in the artery.
  • a 23 G needle was inserted into the cavernous body to measure changes in intra-cavernous pressure (ICP). Both systemic arterial blood pressure and ICP were measured using a pressure transducer (Gilson P23XL-1, physiological pressure transducer, Ohmeda, Canada) connected to a polygraph (Grass Model 7D, Quincy, MA, USA).
  • a pressure transducer Gibson P23XL-1, physiological pressure transducer, Ohmeda, Canada
  • a polygraph Gramss Model 7D, Quincy, MA, USA.
  • PE-10 tube elongated polyethylene tube
  • the tricyclic pteridinone solutions were prepared using a 1% 6N HCI and a 5% DMSO solution.
  • Papaverine (50 mg) + phentolamine (5 mg) (bimix) was prepared in 5 ml with 5% DMSO / remainder saline.
  • Each drug was considered Bolus of 0.1 ml and 0.05 ml heparinized saline infused for rinsing.
  • the basic ICP, ⁇ ICP i.e. the mere change in the basic ICP
  • changes in systemic blood pressure was recorded after intra-arterial injection. All data were assessed using a Student's t test, where p ⁇ 0.05 was considered significant. The data priapic episodes were excluded from the calculations.
  • the tricyclic pteridinone significantly increased the ICP in a dose-dependent manner (FIG. 3). In addition, it was found that the tricyclic pteridinone became one at these higher doses stiff erection. The results clearly show that the tricyclic pteridinone at this cat model of erectile function is an effective drug. The duration of the erectile response was significantly longer than the temporary effect on what blood pressure suggests that efficacy may occur at circulating plasma levels, the nominal have hemodynamic effects.
  • Example 4 Monkey model of male erectile dysfunction
  • the tricyclic pteridinone was administered to Macaca fascicularis monkeys as an intracavernous bolus injection (0.5 ml, with 0.5 ml saline flush).
  • the effects on intracavernous pressure were measured continuously and compared with those of the nitric oxide donor nitroprusside (SNP or NP).
  • SNP or NP nitric oxide donor nitroprusside
  • Nitric oxide induces an erection by acting as a guanylate cyclase agonist.
  • tricyclic pteridinone did not cause a sustained increase in cavernous pressure in monkeys. This may suggest that activation of adenylate and guanylate cyclase activity by neurotransmitters released by parasympathetic and non-adrenergic, non-cholinergic (NANC) nerves (as would be the case with psychogenic or physical stimuli) for enhancement the erectile reaction in this model due to the tricyclic pteridinone is necessary.
  • NANC non-cholinergic

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP02002882A 2001-11-20 2002-02-08 Ptéridinones pour le traitement des dysfonctions érectiles Withdrawn EP1312365A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US98994801A 2001-11-20 2001-11-20
US989948 2001-11-20

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EP1312365A1 true EP1312365A1 (fr) 2003-05-21

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008503515A (ja) * 2004-06-21 2008-02-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規２−ベンジルアミノジヒドロプテリジノン、それらを製造する方法及び薬剤としてのそれらの使用
WO2011079114A1 (fr) * 2009-12-23 2011-06-30 Elan Pharmaceuticals, Inc. Ptéridinones en tant qu'inhibiteurs de polo-like kinase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0429149A1 (fr) * 1989-11-17 1991-05-29 Berlex Laboratories, Inc. Ptéridinones tricycliques et procédé pour leur prÀ©paration
WO2000000212A1 (fr) * 1998-06-26 2000-01-06 Nutracorp Scientific, Inc. Methodes et compositions favorisant l'activite du monoxyde d'azote et du gmp cyclique
WO2001041807A2 (fr) * 1999-12-10 2001-06-14 Vivus, Inc. Administration a travers les muqueuses d'inhibiteurs de la phosphodiesterase dans le traitement de la dyserection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0429149A1 (fr) * 1989-11-17 1991-05-29 Berlex Laboratories, Inc. Ptéridinones tricycliques et procédé pour leur prÀ©paration
WO2000000212A1 (fr) * 1998-06-26 2000-01-06 Nutracorp Scientific, Inc. Methodes et compositions favorisant l'activite du monoxyde d'azote et du gmp cyclique
WO2001041807A2 (fr) * 1999-12-10 2001-06-14 Vivus, Inc. Administration a travers les muqueuses d'inhibiteurs de la phosphodiesterase dans le traitement de la dyserection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAHER A ET AL: "CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IN HUMAN CAVERNOUS SMOOTH MUSCLE", WORLD JOURNAL OF UROLOGY, SPRINGER INTERNATIONAL, DE, vol. 15, no. 1, 1997, pages 32 - 35, XP001021795, ISSN: 0724-4983 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008503515A (ja) * 2004-06-21 2008-02-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規２−ベンジルアミノジヒドロプテリジノン、それらを製造する方法及び薬剤としてのそれらの使用
WO2011079114A1 (fr) * 2009-12-23 2011-06-30 Elan Pharmaceuticals, Inc. Ptéridinones en tant qu'inhibiteurs de polo-like kinase
WO2011079118A1 (fr) * 2009-12-23 2011-06-30 Elan Pharmaceuticals, Inc Ptéridinones en tant qu'inhibiteurs de polo-like kinase
CN102762568A (zh) * 2009-12-23 2012-10-31 伊兰药品公司 作为polo样激酶的抑制剂的蝶啶酮
JP2013515734A (ja) * 2009-12-23 2013-05-09 エラン ファーマシューティカルズ，インコーポレイテッド ポロ様キナーゼの阻害薬としてのプテリジノン
US8445503B2 (en) 2009-12-23 2013-05-21 Elan Pharmaceuticals, Inc. Inhibitors of polo-like kinase
US8541418B2 (en) 2009-12-23 2013-09-24 Elan Pharmaceutical, Inc. Inhibitors of polo-like kinase

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